DNA Sequencing Predicts Melanoma Patients at Risk of Cancer Spread

January 21, 2020 - A DNA sequencing technique analyzes tumors to accurately determine which melanoma patients are at risk for cancer recurrence and spread, according to a study published in Nature Cancer.

In most patients, melanoma begins with a small, pigmented spot on the skin that starts to change. While many primary melanomas can be treated by having this lesion removed, melanoma can often recur and spread.

Providers can analyze the removed lesion to determine the likelihood of the melanoma coming back, but the process is very simplistic, researchers noted. Clinicians analyze the thickness of the lesion, as well as microscopic features such as ulcerations, and assign the lesion a T stage of one through 4.

Immune checkpoint inhibitors, which can reawaken T cells to mount an immune response against cancer cells, have drastically changed the options available to patients whose skin cancer has spread. They can generate dramatic responses in some patients, including long-term remission. However, identifying patients at high risk of recurrence or spread is still an unmet need.

“As recently as 10 years ago the outlook for metastatic melanoma was dismal, but we now have treatments to offer patients with metastatic disease and may also be able to apply these treatments when primary disease hasn’t metastasized,” said corresponding author Thomas Kupper, MD, chair of the Department of Dermatology at the Brigham.

“Because of the advent of these new immunotherapy treatments, it’s important to have a clear idea of which patients are likely to progress so that we can tailor treatment accordingly.”

Researchers set out to find out whether certain measurable features of T cells could predict recurrence in patients whose primary melanoma had been removed and were free of disease. T1 melanomas, or those less than one millimeter, rarely metastasize, so the team focused on T2 (one to two millimeters), T3 (two to four millimeters), and T4 (greater than four millimeters) primary melanomas.

The team compared samples from patients whose primary melanoma progressed to metastatic disease to patients whose primary melanoma did not. Researchers used high-throughput DNA sequencing to analyze the T cell repertoire of the tumors.

The group found that of all the variables identified, the T-cell fraction (TCFr, the proportion of cells in the lesion that were T cells) was a powerful predictor of which patients would progress. Even for patients whose lesion thickness was the same, TCFr was able to predict which patients were more likely to have metastatic disease.

Patients with a TCFr lower than 20 percent were more at risk of disease progression than patients with a TCFr higher than 20 percent. For example, for patients with T3 melanoma, five years after having their primary lesion removed, 51 percent of those with lower TCFr experienced recurrence, compared to just 24 percent with higher TCFr.

The DNA sequencing method is not yet ready for use in clinical settings, researchers stated. Additionally, because the study was retrospective, researchers will need to conduct prospective studies to further validate the test. The team is confident that if brought to the clinic, the DNA sequencing technique could significantly improve predictive models and cancer treatment.

“This is a simple, elegant test. It’s quantitative rather than subjective, and it may be able to add value to predictions about disease progression,” said Kupper. “In the future, such a test could help us tailor treatment; patients with high TCFr may further benefit from checkpoint inhibitor therapy, while low TCFr patients may need additional intervention.”